To proceed toward our long-term objectives to understand the physiology of glucose counterregulation and its pathophysiology in insulin dependent diabetes mellitus (IDDM) in sufficient detail to permit development of strategies that will effectively eliminate hypoglycemia from their lives, and to expand the knowledge base of human metabolic physiology and pathophysiology, we plan to test a series of hypotheses relevant to five aims: 1. To dissect further the physiological mechanisms of glucose counterregulation. 2. To explore physiological regulation of cerebral blood flow and glucose transport into the brain, and their potential pathophysiological regulation in IDDM. 3. To define the effects of hypoglycemia on cognitive function and determine the mechanisms of awareness of hypoglycemia. 4. To learn to prevent, correct or compensate for defective glucose counterregulation, and thus to reduce the frequency of iatrogenic hypoglycemia in IDDM. 5. To validate further methods for measuring sympathetic neural activity and to study the role of the sympathochromaffin system in the pathophysiology of IDDM. We will study normal persons, patients with panhypopituitarism and patients with IDDM, often with the latter stratified vis-a-vis metabolic control or classic autonomic neuropathy versus defective counterregulation/ hypoglycemia unawareness. We will quantitate plasma levels of metabolic regulatory hormones (insulin, glucagon, epinephrine, growth hormone and cortisol), markers (C-peptide, norepinephrine, pancreatic polypeptide) and substrates/intermediates (glucose, FFA, glycerol, beta-hydroxybutyrate, lactate and alanine), often with kinetic measurements (e.g. glucose, NE); in some studies cellular glucose transporters will be measured. The metabolic environment will be controlled with clamp techniques. Conditions will include the basal state, hypoglycemia, standing, exercise and interventions with counterregulatory hormones, autonomic antagonists and agonists and an amino acid. Endpoints, in addition to glucose concentration and counterregulatory hormone responses, will include positron emission tomography measurements of glucose transport into the brain and cerebral blood flow, quantitation of symptoms, awareness of hypoglycemia and cognitive function; and measurements of norepinephrine kinetics.